1. Field of the Invention
The invention relates to composition and methods for the treatment of cancer.
2. Description of Related Art
Prior Art:
Currently, surgery accounts for around 80% of the curative benefit in the roughly 50% of people that survive cancer today. Chemotherapy and radiation account for the balance. The curative value of chemotherapy as used under prior art is minimal at best. Advanced stage cancers, which rely primarily on chemotherapy for a cure, indicate just how modest chemotherapy's contribution is under prior art: the 5 year survival rate for Stage 1V metastatic lung cancer is 1%, Stage 1V metastatic colon cancer is 5%, pancreatic cancer is 2%, and Stage 1V metastatic breast cancer is 14% (Harrison's 15th ed. pgs. 565, 584, 591, 575 respectively). Clearly, prior art is in dire need of curative chemotherapeutic regimens. The present invention provides them.
Harrison's Principles of Internal Medicine (14th ed. p. 527-536) outlines prior art chemotherapeutic drug treatments used for cancer.
Most chemotherapeutic agents in use today are cell cycle active; that is, they are cytotoxic mainly to actively cycling cells. In addition, most cell cycle active agents are phase specific; that is, they are cytotoxic to cells in a particular phase of the cell cycle. Of the 44 commonly used chemotherapeutics listed in Harrison's (15th ed.), more than 70% are phase specific, primarily S-phase specific.
Alkylating agents are among the most widely used anti tumor agents and are efficient at cross-linking DNA, leading to strand breakage. Alkylating agents include cyclophosphamide, ifosfamide, melphalan, busulfan, mechlorethamine (nitrogen mustard), chlorambucil, thiotepa, carmustine, lomustine as well as platinum compounds such as cisplatin and carboplatin, which are not true alkylating agents also lead to covalent cross linking of DNA. These agents are best regarded as cell-cycle active but non-phase specific.
Purine/pyrimidine analogs/antimetabolites induce cytotoxicity by serving as false substrates in biochemical pathways. They are cell cycle active and specific mainly for the S phase. They include cytarabine, fluorouracil, gemcitabine, cladribine, fludarabine, pentostatin, hydroxyurea, and methotrexate.
Topoisomerase inhibitors interfere with the enzymes topoisomerase 1 and topoisomerase 2, responsible for mediating conformational and topological changes in the DNA required during transcription and replication. These agents include daunorubicin, doxorubicin, idarubicin, etoposide, teniposide, dactinomycin, and mitoxantrone. They are S-Phase specific.
Plant Alkaloids include vincristine, vinblastine, and vinorelbine which inhibit microtubule assembly by binding to tubulin and docetaxel and paclitaxel which function by stabilizing microtubules and preventing their disassembly. They are cell cycle active and cytotoxic predominately during the M phase of the cell cycle.
Antitumor Antibiotics include bleomycin that induces DNA strand breakage through free radical generation and Mitomycin C which cross links DNA. They are cytotoxic mainly during the G2 and M phase.
Other Agents include dacarbazine and procarbazine which act as alkylating agents to damage DNA and L-Asparaginase, the only enzyme used as a anti tumor agent, which acts by depletion of extracellular pools of asparagine.
Therapeutic Index Dosaging:
Chemotherapeutic agents exhibit a dose response effect. At sufficiently low concentrations no cytotoxicity is observed. At increasing concentrations, cell kill is proportional to drug exposure. At high concentrations, the effect reaches a plateau. Drugs that are cell cycle active, but not phase specific, such as alkylating agents, characteristically have steep dose response curves: An increase in the drug concentration by an order of magnitude or more results in a proportional increase in tumor cell kill. By contrast, the dose response curve of phase specific agents, such as the antimetabolites, typically is linear over only a narrow range. These agents are less suitable for dose escalation and increased tumor cell kill is observed after prolonged exposure as a larger percentage of the tumor cells enter the cell cycle.
Chemotherapy employs two principles in administration: Therapeutic Index Dosaging and Cyclical Administration (HPIM 14th ed. 527-528 Pharmocodynamics section).
The therapeutic index represents the difference between the response of the tumor and response of normal tissue for a given dose of chemotherapeutic. Normal cells are also susceptible to the cytotoxic effects of chemotherapeutic drugs and exhibit a dose-response effect, but the response curve is shifted relative to that of malignant cells (see HPIM 14th ed. P. 528, FIG. 86-3 enclosed). This difference represents the therapeutic index. The toxicity to normal tissue that limits further dose escalation is the “dose-limiting toxicity”. The dose just below this point is the “maximum tolerated dose”. Proliferative normal tissues such as the bone marrow and gastrointestinal mucosa are generally the most susceptible to chemotherapy-induced toxicity. The usefulness of many chemotherapeutics is limited by the fact that they have a narrow therapeutic index.
Skipper Log Cell Kill Model
Tumor regression in response to chemotherapy is logarithmic. The “tumor kill rate” (TKR) as used in this application is hereby defined as the percentage of cells of a tumor that are killed during one administration cycle of a chemotherapeutic. The “phase kill rate” (PKR) as used in this application is hereby defined as the percentage of cells in a given phase of the cell cycle that are killed by a single administration of a phase specific chemotherapeutic. As an example, if a 99% S-phase kill rate chemo is administered, and 32% of the cells are in the S-phase, the tumor kill rate will be 31.7% (i.e. 0.99×0.32) if only one administration is given. If 4 administrations are given in a cycle and are rationally timed to the progression of new cells into the S-Phase, and the susceptible phase in the incoming batch of cancer cells remains synchronized to each chemotherapeutic administration, then the tumor kill rate will equal the phase kill rate.
Conventional methods typically focus on “maximum tolerated doses” and extended administration periods. Cyclical administration is required to allow normal rapidly proliferating cell populations to recover from the effects of chemotherapy. The number of administration cycles required to completely eradicate a tumor is dependent on the tumor kill rate of the therapeutic. To completely eradicate a tumor it is necessary to get below the mathematical 1 surviving cell number. As an example, to kill a 10 billion cell tumor with a chemotherapeutic that kills 95% of the tumor cells each administration cycle (5% survive) would require 8 cycles of chemotherapy (i.e. 10,000,000,000×0.05×0.05×0.05×0.05×0.05×0.05×0.05×0.05=0.39). In contrast, a chemotherapeutic with a 50% tumor kill rate would require 34 administration cycles to get the 10 billion cell tumor below the one surviving cell number (i.e. 10,000,000,000×0.5 (34 times)=0.58). Likewise a 99% tumor kill rate would require only 6 administration cycles to get the 10 billion cell tumor below the one surviving cell number. The Skipper log cell kill model does not allow for tumor growth between administration cycles.
Combination Chemotherapy:
Under prior art most cancers are treated with combination chemotherapy (HPIM 14th ed. p. 531-532) in an attempt to boost curative result. The underlying principles are that 1) each agent should have an independent activity against a specific tumor, 2) each drug should have a different mechanism of action (MOA), 3) there should be no cross resistance among the agents used, and 4) each agent should have a different dose-limiting toxicity profile.